This application is the xc2xa7371 national stage entry of PCT/EP99/02308, filed Mar. 30, 1999.
The present invention relates to a novel process for the preparation of purine derivatives and novel intermediate compounds used in this process.
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28402 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the xe2x80x98bromoesterxe2x80x99 route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carboxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.
A disadvantage of this route to famciclovir and penciclovir is that the initial alkylation reaction with the bromotriester reagent gives a mixture of the N-9 and N-7 isomers. 2-Amino-6-chloropurine is a fairly expensive starting material, and accordingly the wastage arising from the production of the unwanted N-7 isomer is undesirable.
EP-A-0352953 discloses a process for the production of purine derivatives according to the bromotriester route in which the ratio of N-9 to N-7 products is improved by converting the 2-amino-6-chloropurine to the analogous 6-iodo, 6benzylthio or 6-(phenacylmethyl)thio compound.
Whilst the process of EP-A-0352953 represents an improvement in the bromotriester process for producing famciclovir, it suffers from the disadvantages that a material quantity of the N-7 isomer still results, and moreover an additional step of converting the 6-chloro substituent to 6-iodo, 6-benzylthio or 6-(phenacylmethyl)thio is required.
Accordingly, there remains a need for an improved process for making purine derivatives such as famciclovir and penciclovir.
According to one aspect of the invention there is provided a process for the production of a compound of formula (I): 
wherein X is H, OH or halo; and R1 and R2 are selected independently from C1-12 alkyl, aryl, C1-12 alkylaryl, C1-12 alkylsilyl, arylsilyl and C1-12 alkylarylsilyl, or R1 and R2 are joined together to form a cyclic acetal or ketal; which process comprises reacting a compound of formula (II): 
wherein X is as defined for formula (I), with a compound of formula (III): 
wherein Y is a leaving group and R1 and R2 are as defined for formula (I), in the presence of a palladium(0) catalyst and a ligand.
Preferably X is halo, more preferably X is chloro.
R1 and R2 may be selected independently from benzyl and C1-12 alkyldiarylsilyl, such as C1-6 alkyldiphenylsilyl, e.g. t-butyldiphenylsilyl. Preferably however, R1 and R2 are linked to form a cyclic acetal or ketal, preferably a 6-membered cyclic acetal or ketal of formula (IV): 
wherein R3 and R4 are selected independently from H, C1-12 alkyl and aryl.
Preferably R3 and R4 are both C1-12 alkyl, more preferably R3 and R4 are both methyl.
The palladium (0) catalyst may be selected from tetrakis(triphenylphosphine) palladium(0), tris(dibenzylideneacetone)dipalladium(0) chloroform or any palladium(0) dibenzylidene catalyst. More generally it is envisaged that any palladium(0) source may be suitable.
Alternatively the palladium(0) catalyst may be formed in situ from a palladium(II) salt. The salt may be selected from palladium acetate, palladium chloride, allyl palladium chloride dimer, bis(triphenylphosphine) palladium chloride and [1,2-bis(diphenylphosphino)ethane]dichloropalladium (II).
The ligand may be selected from the group consisting of triphenylphosphine; tributylphosphine; tricyclohexylphosphine; bis(diphenylphosphino)methane; 1,2-bis(diphenylphosphino)ethane; 1,3-bis(diphenylphosphino)propane; 1,4-bis(diphenylphosphino)butane; 1,2-bis(diphenylphosphino)ferrocene; (R)-(+)-2,2xe2x80x2 bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; 3,3xe2x80x23xe2x80x3-phosphinidynetris(benzenesulphonic acid) trisodium salt; trimethyl phosphite; triisopropyl phosphite; triphenyl phosphite, trimethylolpropane phosphite, tri-2-furylphosphine and tris(4-methoxyphenyl)phosphine.
Preferably, the ligand is selected from 1,2-bis(diphenylphosphino)ethane [DIPHOS], trimethylolpropane phosphite [TMPP] and 1,3-bis(diphenylphosphino)propane [DPPP].
The reaction between the compound of formula (II) and the compound of formula (III) may additionally be conducted in the presence of a base. The base may selected from caesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, cesium fluoride, lithium hydride, sodium hydride, sodium hydroxide, triethylamine, diazabicyclo[5.4.0] undec-7-ene and 1,1,3,3-tetramethylguanidine. The base is preferably caesium or potassium carbonate.
Where the catalyst is provided in the form of a palladium(II) salt, which is reduced to palladium(0) in situ, the reaction may be effected by the phosphine or phosphite ligand, or by the use of an additional reducing agent. It has been found, for example, that the TMPP ligand is capable of reducing the palladium(II) salt to palladium(0) to give a good N-9 to N-7 ratio. The additional reducing agent may be selected from hydrazine and sodium hypophosphite.
The reaction will usually be conducted in an inert solvent. The inert solvent may be selected from the group consisting of dimethylformamide (DMF), diethylformamide, N-methylpyrrolidinone, dimethylacetamide, dimethylsulphoxide, acetonitrile, tetrahydrofuran, aqueous methanol, aqueous acetonitrile and aqueous dimethylformamide. Preferably the inert solvent comprises DMF.
The reaction may be carried out at a temperature in the range of about 20-120xc2x0 C., preferably about 60-80xc2x0 C., for 1-50 hours depending on the reagents used, preferably 1-24 hours.
The reaction may be conducted under an inert atmosphere. Any suitable inert gas may be used, but argon is preferred. Preferably the reaction is carried out under a flow of the inert gas.
Further additives may be included in the reaction mixture, which additives are selected from hydrazine hydrate, benzyltrimethylammonium chloride, tetrabutylammonium chloride, magnesium iodide, Aliquat 336, barium acetate, lithium chloride, 15-Crown-5, ammonium formate, sodium acetate, sodium hypophosphite hydrate and n-butyllithium.
The reaction may be performed by adding the palladium catalyst to a reaction mixture containing the compounds of formulae (II) and (III), the ligand and any additional reagents, such that the ligated catalytic species is formed in situ. However, pre-formation of the ligated catalytic species is preferred. Pre-formation may be achieved by stirring the palladium catalyst and the ligand in the reaction solvent, e.g. for a period of up to 30 min, prior to the addition of the compounds of formulae (II) and (III) and any additional reagents.
It has been found surprisingly that the reaction between compounds of formulae (II) and (III) in accordance with the present invention gives rise to a very high yield of the N-9 isomer over the unwanted N-7 isomer.
In a further aspect of the invention there is provided a compound of formula (I) which is a novel intermediate wherein X, R1 and R2 are as defined above.
In another aspect of the invention there is provided a process for the production of a compound of formula (V): 
wherein Xxe2x80x2 is H or OH; and R5 and R6 are independently selected from H and Rxe2x80x2CO wherein Rxe2x80x2 is phenyl, C1-12 alkyl or phosphoryl, which process comprises producing a compound of formula (I) according to the process of the invention defined above, hydrogenating the compound of formula (I), converting xe2x80x94OR1 and xe2x80x94OR2 to form two hydroxy groups and thereafter if and as necessary:
(i) converting one or both of the hydroxy groups on the resulting 4-hydroxy-3-hydroxymethylbut-1-yl moiety to form compounds in which R5 and R6 represent Rxe2x80x2CO; and/or
(ii) converting X to Xxe2x80x2.
Preferably R5 and R6 are both hydrogen or acetyl. Where Xxe2x80x2 is H and R5 and R6 are both acetyl the compound of formula (V) is famciclovir. Where Xxe2x80x2 is OH and R5 and R6 are both H the compound of formula (V) is penciclovir.
Hydrogenation of the ethylidene moiety may be effected by hydrogenation of the compound of formula (I) in the presence of a catalyst, preferably a palladium catalyst, such as palladium on charcoal. Other suitable catalysts are Pd/CaCO3 and Pd(OH)2/C. The hydrogenation may be carried out in a solvent selected from the group consisting of alkyl esters e.g. ethyl acetate, tetrahydrofuran, and C1-6 alkyl alcohols e.g. methanol or ethanol.
Optionally a base is included in the reaction mixture. The base may be selected from triethylamine, sodium acetate, potassium hydroxide, aqueous sodium hydroxide and basic alumina. Alternatively a basic ion exchange resin may be employed. Hydrogenation may be carried out at elevated temperature and pressure or, alternatively, at room temperature and atmospheric pressure. As mentioned above, X is preferably halo such as chloro. In accordance with an important aspect of the invention, hydrogenation of the compound of formula (I) in the presence of a base reduces both the chloro moiety (to H) at the 6-position on the purine ring and also the double bond. This one step reduction of the 6-chloro and ethylidene groups represents a particularly advantageous synthetic route to famciclovir. The reduced product may be isolated if required. In the absence of base, only the double bond is reduced. Subsequent hydrolysis of the 6-chloro group and xe2x80x94OR1 and xe2x80x94OR2 then affords penciclovir. Therefore, the choice of whether or not to use a base allows the synthesis of either famciclovir or penciclovir.
xe2x80x94OR1 and xe2x80x94OR2 may be converted to xe2x80x94OH by any suitable method known to those skilled in the art. Cyclic acetals or ketals are preferably hydrolysed using tetrahydrofuran/methanol and hydrochloric acid. Where R1 and R2 are benzyl, then hydrogenation may be used.
In a particularly preferred embodiment of this aspect of the invention, the two hydroxy groups of the 4-hydroxy-3-hydroxymethylbut-1-yl group are acylated. Any convenient acylation method known to those skilled in the art may be used, but preferably acetic anhydride is employed.
The 2-amino group on the purine ring may be protected throughout using conventional protecting groups such as benzyl, acetyl or a Schiff""s base.
Various of the compounds of formula (III) are novel, thus according to a further aspect of the invention there is provided a compound of formula (III): 
wherein Y is a leaving group and R1 and R2 are are joined together to form a cyclic acetal or ketal.
A preferred group of compounds of formula (III) are those of formula (IV): 
wherein Y is a leaving group and R3 and R4 are selected independently from H, C1-12 alkyl and aryl. Preferably R3 and R4 are both C1-12 alkyl, more preferably R3 and R4 are both methyl.
A particular compound of formula (III) that may be mentioned is methyl 2,2-dimethyl-5-ethenyl-1,3-dioxane-5-carbonate.
The compounds of formula (III) may be prepared by reacting a compound of formula (VI): 
wherein R1 and R2 are as defined for formula (I), with a vinyl carbanion and thereafter converting the resulting alkoxide to the leaving group Y.
The vinyl carbanion may be a Grignard reagent such as vinylmagnesium bromide.
The nucleophilic addition of the vinyl carbanion to the compound of formula (VI) may be carried out in an inert solvent such as tetrahydrofuran, at a temperature of less than about xe2x88x9260xc2x0 C., preferably about xe2x88x9278xc2x0 C.
The leaving group Y may be selected from the group consisting of C1-6 alkyl- or aryl carbonates e.g. methyl carbonate or phenyl carbonate, C1-6 acyloxy e.g. acetate or trifluoroacetate, and C1-6 alkylphosphates e.g. diethylphosphate. A C1-6 alkyl carbonate is preferred however because it gives rise to volatile side products when reacted with the compound of formula (II). The leaving group may be introduced by, for example, quenching the reaction between the compound of formula (VI) and the vinyl carbanion with a C1-6 alkyl chloroformate, e.g. methyl chloroformate, if desired. The 5-vinyl-5-hydroxy intermediate formed by reaction of the vinyl carbanion with the compound of formula (VI) may be isolated before the leaving group Y is introduced. The compound of formula (III) may be isolated and purified by known methods. Alternatively, the compound of formula (III) may be used as a crude oil without purification.
Unless otherwise stated, any of the alkyl groups mentioned above may comprise 1-12 carbon atoms, preferably 1-6 carbon atoms. Alkyl groups may be straight or branched chain, or cyclic. Cyclic alkyl groups preferably comprise 3-8 carbon atoms. Any alkyl groups may be substituted by one or more fluoro atoms.
Any of the aryl groups mentioned above preferably comprise 5-10 carbon atoms and may be mono- or bicyclic. Suitable aryl groups included phenyl and naphthyl, preferably phenyl.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.